Deficiency of serine sulfhydrase means that a special body enzyme called cystathionine-beta-synthase (CBS) does not work properly or is missing. This enzyme normally changes two amino acids, homocysteine and serine, into another amino acid called cystathionine, which is later turned into cysteine. When the enzyme is weak or absent, homocysteine builds up in the blood and urine and harms many organs such as the eyes, bones, brain, and blood vessels, causing a disorder known as classic homocystinuria.
This problem is usually genetic. It happens when a child receives a faulty copy of the CBS gene from both parents (autosomal recessive pattern). Because the enzyme works poorly, the body cannot handle sulfur amino acids correctly, so toxic homocysteine levels rise, while helpful cysteine may become low. Over time, this can lead to poor growth, bone changes that look like Marfan syndrome, blood clots, eye lens dislocation, and learning or behavior problems.
“Deficiency of serine sulfhydrase” is an older name for cystathionine-β-synthase (CBS) deficiency, the classic form of homocystinuria.[1] In this inherited disorder, the CBS enzyme—also called serine sulfhydrase—cannot properly convert the amino acid homocysteine and serine into cystathionine in the trans-sulfuration pathway.[2][3] As a result, homocysteine and methionine build up, while cystathionine and cysteine may be relatively low, damaging blood vessels, eyes, bones and the brain over time.[4][5]
CBS deficiency is usually autosomal recessive, meaning a child must inherit a faulty CBS gene from both parents.[6] Symptoms may include severely short-sighted vision, lens dislocation (ectopia lentis), tall thin body with long limbs, osteoporosis, spine and chest deformities, developmental delay, learning or behavior problems, and dangerous blood clots causing stroke, deep-vein thrombosis or pulmonary embolism.[7][8] Early diagnosis through newborn screening or targeted testing, plus strict treatment to lower homocysteine, can prevent many complications and allow near-normal life in many patients.[9][10]
CBS (serine sulfhydrase) uses vitamin B6 (pyridoxine) as a cofactor to do its job. Some people with this enzyme deficiency improve when they take high doses of vitamin B6, because the extra cofactor helps the remaining enzyme work a little better. Others do not respond because their CBS enzyme is too damaged. This difference is important for treatment and for how severe the disease becomes.
Other names
Deficiency of serine sulfhydrase is most often called cystathionine-beta-synthase (CBS) deficiency. It is also known in clinics and textbooks as homocystinuria due to CBS deficiency, homocystinuria type I, or classic homocystinuria. The enzyme itself has several older names, including serine sulfhydrase, beta-thionase, methylcysteine synthase, and L-serine hydro-lyase (adding homocysteine). These names all describe the same basic enzyme activity and are grouped under the official enzyme code EC 4.2.1.22.
Types of serine sulfhydrase (CBS) deficiency
There is a vitamin B6-responsive type. In this type, the CBS enzyme still has some activity, but it needs extra help from vitamin B6. When doctors give high-dose pyridoxine, homocysteine levels drop, and symptoms may be milder or appear later. Children with this type often have better long-term outcomes if treated early.
There is a vitamin B6-non-responsive type. In this type, the gene change damages the CBS enzyme so badly that giving more vitamin B6 does not improve its work. These patients usually have higher homocysteine levels, more severe symptoms, and need stricter diet and other medicines to lower homocysteine.
Doctors sometimes describe early-onset disease when symptoms begin in infancy or early childhood. These children may show developmental delay, lens dislocation, or bone changes before school age. Early start often means more risk of blood clots and eye problems if the condition is not found and treated quickly.
There is also a late-onset or mildly symptomatic type. In these people, CBS activity is reduced but not completely absent, so homocysteine may be high but symptoms are subtle for many years. They might first present as teenagers or adults with blood clots, mild learning problems, or osteoporosis, and are sometimes diagnosed only after screening relatives of a known case.
Causes
CBS gene mutations (main cause)
The most important cause is a harmful change (mutation) in both copies of the CBS gene. These mutations reduce the amount or function of the CBS enzyme, leading directly to serine sulfhydrase deficiency and homocystinuria. This is an inherited autosomal recessive condition, so both parents are usually healthy carriers.Missense mutations in CBS
Some mutations change just one amino acid in the CBS protein (missense). This can alter the shape of the enzyme so it works more slowly, becomes unstable, or cannot bind vitamin B6 correctly. Depending on the specific mutation, the enzyme defect can be mild or severe and may determine whether the person is B6-responsive.Nonsense or frameshift mutations
Other people have mutations that create a stop signal too early or shift the reading frame of the gene. These changes often lead to a very short, non-working CBS protein or no protein at all. This usually causes severe enzyme deficiency and high homocysteine levels from early life.Splice-site and regulatory mutations
Some mutations affect how the CBS gene is processed (splicing) or how strongly it is turned on (promoter regions). Even if the protein sequence is normal, reduced gene expression can lower the total amount of CBS enzyme, resulting in functional serine sulfhydrase deficiency.Consanguinity (parents related by blood)
When parents are related (for example, cousins), they are more likely to carry the same CBS gene mutation. This increases the chance their child receives both mutated copies and has CBS deficiency. Thus, consanguineous marriages raise the risk of autosomal recessive disorders, including serine sulfhydrase deficiency.Vitamin B6 deficiency as a worsening factor
A true CBS deficiency is genetic, but low vitamin B6 levels can make the enzyme work even less efficiently. In a person with partial CBS activity, poor dietary intake, malabsorption, or certain drugs that lower vitamin B6 can worsen homocysteine buildup and bring on symptoms earlier.Deficiency of folate (vitamin B9)
Folate is needed for the “remethylation” pathway that converts homocysteine back to methionine. If folate levels are low, this backup pathway is weaker, so homocysteine rises even more in someone with CBS deficiency. Folate deficiency therefore acts as a modifying cause, worsening the biochemical imbalance.Vitamin B12 deficiency
Vitamin B12 is also needed for remethylation of homocysteine. Without enough B12, homocysteine removal slows down, so people with partial CBS activity may show higher homocysteine levels and more symptoms. This does not create CBS deficiency, but it aggravates the metabolic problem.Very high methionine intake
Methionine is an essential amino acid found in protein foods. In CBS deficiency, methionine is turned into homocysteine, but the pathway from homocysteine to cystathionine is blocked. A very high protein or methionine-rich diet can push more homocysteine into an already blocked system, increasing toxicity.Liver disease
CBS is mainly active in the liver. If liver cells are damaged by disease, even a normal CBS gene may not produce enough working enzyme. In a person who already has CBS deficiency, additional liver damage can further reduce enzyme activity and worsen the biochemical picture.Kidney dysfunction
The kidneys help clear homocysteine and related compounds from the blood. When kidney function is reduced, homocysteine stays in the circulation longer. In someone with CBS deficiency, kidney disease can therefore raise homocysteine even more and increase the risk of clots and vascular damage.Drugs that interfere with vitamin metabolism
Some medicines interfere with vitamin B6, B12, or folate handling in the body. In patients with CBS deficiency, these medicines can tip the balance toward higher homocysteine by limiting cofactor supply to remaining metabolic pathways. Doctors try to avoid such drugs or monitor levels carefully.Poor overall nutrition
Children or adults with very low protein quality, little vitamin intake, or chronic malnutrition may have weaker enzyme function and less tolerance for metabolic stress. In a person with an underlying CBS defect, poor diet can therefore increase symptoms and slow growth and development.Concurrent genetic variants in folate or B12 pathways
Some people carry additional variants in genes involved in folate or B12 metabolism, such as MTHFR and related enzymes. These changes can further reduce the ability to recycle homocysteine and can modify the severity of CBS deficiency, even though they are not the primary cause.Oxidative stress and inflammation
High homocysteine itself increases oxidative stress and damages blood vessel lining. Chronic inflammation, smoking, or other illnesses can further increase oxidative load. This can worsen tissue injury in someone who already has CBS deficiency and high homocysteine, acting as a harmful background factor.Down syndrome with altered CBS expression (opposite direction)
In Down syndrome, there can be extra copies of the CBS gene on chromosome 21, leading to overexpression of the enzyme and low homocysteine. Although this is not a deficiency, it shows how changes in CBS gene dosage change sulfur amino acid metabolism and helps explain why missing or weak CBS in classical homocystinuria has the opposite effect.Lack of newborn screening programs
In many regions, the main “cause” of severe disease is late diagnosis because newborn screening for homocystinuria is not done or not available. Without early detection, the genetic defect remains hidden until major symptoms like clots or eye problems appear. Early screening reduces but does not remove genetic risk.Poor access to medical care
Even after symptoms begin, some families cannot reach specialists or testing. Delay in getting the right diagnosis and treatment allows homocysteine levels to stay high for years, causing preventable complications. This social factor does not cause the mutation, but strongly influences disease burden.Non-adherence to low-methionine diet
Treatment for CBS deficiency often includes a low-methionine, special formula diet. If a patient cannot follow this plan, homocysteine levels rise again, and symptoms or complications may return or worsen. This makes long-term management and family education very important.Inadequate monitoring and follow-up
Even when treatment is started, lack of regular blood tests and dose adjustments can lead to periods of poor control. If vitamin doses or diet are not changed as the child grows, homocysteine may stay high and cause damage, acting as a preventable cause of complications in CBS deficiency.
Symptoms and signs
Developmental delay and learning problems
Many children with serine sulfhydrase (CBS) deficiency are slow to reach milestones such as speaking, understanding, or school learning. They may have intellectual disability of various degrees if homocysteine is high for a long time. Early diagnosis and treatment can reduce, but not always prevent, these problems.Behavior and psychiatric symptoms
Some patients show behavior changes such as hyperactivity, attention problems, anxiety, or mood swings. In older children and adults, depression, psychosis, or personality changes can appear. These features are thought to be related to toxic effects of homocysteine on the brain and blood vessels.Seizures
Seizures can happen in CBS deficiency, especially in untreated or late-treated patients. They may present as staring spells, jerking movements, or more severe generalized seizures. Abnormal electrical activity in the brain is likely triggered by long-term metabolic stress and vascular damage.Ectopia lentis (lens dislocation)
One of the hallmark signs is displacement of the eye lens, often downward and inward, unlike Marfan syndrome where it is usually upward. This can cause blurred vision, double vision, or early severe short-sightedness and may be detected on eye exam before other signs appear.Severe myopia (short-sightedness)
Even without full lens dislocation, many children develop high degrees of myopia at a young age. This can affect school performance and daily life and may be the first reason they are sent to an eye specialist, who then notices other features of homocystinuria.Marfanoid body build
People with CBS deficiency often look tall and thin with long arms, legs, fingers, and a narrow face. This “marfanoid habitus” comes from abnormal bone growth and resembles Marfan syndrome, but the cause is different, and homocysteine is high.Chest and spine deformities
The breastbone may sink in (pectus excavatum) or stick out (pectus carinatum), and the spine may curve sideways (scoliosis). These skeletal changes develop gradually as the child grows and reflect disturbed collagen and bone structure related to high homocysteine.Osteoporosis and bone fragility
Abnormally thin and weak bones are common in CBS deficiency, even in teenagers and young adults. This can cause bone pain, fractures after mild trauma, and poor posture. Removing homocysteine and giving proper nutrition and vitamins can help improve bone density.Joint problems and long fingers (arachnodactyly)
Fingers may be very long and slim, and joints can be either too flexible or stiff. Some people develop contractures or joint pain. These changes again resemble Marfan syndrome and are linked to altered connective tissue proteins under the influence of high homocysteine.Blood clots in veins or arteries (thromboembolism)
One of the most dangerous symptoms is formation of clots in deep veins, lungs, brain, or other vessels. These clots can cause stroke, pulmonary embolism, or other life-threatening problems, sometimes even in children or young adults. Thromboembolism is a major cause of illness and death in untreated CBS deficiency.Weakness, fatigue, and poor exercise tolerance
Children and adults may feel tired easily, have low stamina, or complain of muscle weakness. This can be due to a mix of anemia, poor nutrition, bone pain, and vascular problems from the underlying metabolic disorder.Headache and migraine-like pain
Recurrent headaches can occur because high homocysteine affects blood vessels in the brain and may change blood flow. In some patients, headaches improve when homocysteine levels are lowered by treatment, suggesting a direct link.Growth problems
Some children with CBS deficiency are excessively tall, while others may have poor weight gain or short stature if nutrition is poor or if severe illness occurs. Growth patterns can therefore be abnormal in either direction and need careful monitoring.Skin and hair changes
High homocysteine and low cysteine levels can change skin and hair texture. Some patients may have thin, brittle hair or dry, pale skin, partly due to nutritional limitations in their treatment diet and the metabolic disorder itself.Stroke-like episodes and neurologic deficits
Young people with CBS deficiency may suddenly develop weakness on one side, speech difficulty, or other stroke-like symptoms due to blood clots in brain arteries. Even if they recover, they may have lasting neurologic problems unless the underlying metabolic issue is treated.
Diagnostic tests
Doctors use a mix of physical examination, bedside manual tests, laboratory and pathological studies, electrodiagnostic tests, and imaging tests to diagnose serine sulfhydrase (CBS) deficiency and check its effects. The exact combination depends on the person’s age, symptoms, and local resources, but blood homocysteine measurement and CBS gene testing are central.
Physical examination tests
General physical exam with growth and body build assessment
The doctor measures height, weight, head size, and body proportions and looks for tall, thin marfanoid build, long limbs, and long fingers. They also check the chest and spine for deformities and look for signs of poor nutrition or delayed puberty. These observations give early clues that a systemic connective tissue and metabolic problem may be present.Eye examination with basic tools
Even before using special machines, the doctor uses a light and simple tools to look at the front of the eye and the position of the lens. If the lens looks displaced or mobile, or if the pupil appears irregular, this strongly suggests ectopia lentis, a key sign of CBS deficiency-related homocystinuria.Cardiovascular and neurologic bedside exam
The doctor checks heart rate, blood pressure, and pulses, and listens to the heart and lungs for signs of clots or heart strain. A basic neurologic exam checks strength, reflexes, coordination, and speech. Abnormal findings may point toward previous silent strokes or clots, which are common complications of long-standing high homocysteine.
Manual tests (bedside functional tests)
Visual acuity testing with a chart
Reading letters or symbols on an eye chart tests how clearly the patient can see. Very poor vision, especially in a child or teenager, may reflect severe myopia or lens problems. If glasses do not correct the vision as expected, this raises suspicion for lens dislocation and leads to more detailed eye tests.Joint mobility and flexibility tests
The doctor gently bends and straightens joints, including fingers, wrists, elbows, knees, and spine, to check if they are overly flexible or stiff. Long, thin fingers (arachnodactyly) and abnormal joint motion fit with marfanoid skeletal features seen in CBS deficiency and help distinguish it from other causes of homocysteine elevation.Simple neurologic manual tests for coordination and balance
Tasks like walking on a straight line, touching nose then finger, or standing with eyes closed help assess coordination and balance. Problems with these tasks may reflect stroke damage, seizures, or other brain involvement due to chronic hyperhomocysteinemia in CBS deficiency.
Laboratory and pathological tests
Plasma total homocysteine level
This is the key screening test. Blood is drawn and total homocysteine in plasma is measured. In untreated CBS deficiency, levels are usually very high, often many times above normal. After treatment, doctors aim to keep homocysteine much lower to reduce the risk of clots and organ damage.Plasma methionine concentration
Methionine levels are also measured in the same blood sample. In CBS deficiency, methionine often becomes elevated because the pathway from homocysteine toward cystathionine is blocked, so more methionine is formed. This pattern (high homocysteine plus high methionine) supports the diagnosis of CBS enzyme deficiency.Urine amino acid analysis (aminoacidogram)
A urine sample is analyzed for amino acids using chromatography. In CBS deficiency, homocystine (a form of homocysteine) is often present in high amounts in urine. This finding is the basis of the name “homocystinuria” and remains an important diagnostic clue, especially in settings without advanced gene testing.CBS gene sequencing (molecular genetic testing)
Genetic testing looks directly at the CBS gene to find disease-causing mutations. Sequencing can identify missense, nonsense, splice-site, or small insertion/deletion changes. Confirming two harmful CBS variants proves the diagnosis, helps predict vitamin B6 response, and allows carrier testing and prenatal diagnosis in the family.Measurement of vitamin B6, B12, and folate levels
Blood levels of these vitamins are checked to see if there are additional deficiencies that could worsen homocysteine levels. Low B6, B12, or folate may need correction to optimize treatment, and normal levels help separate primary CBS deficiency from other causes of hyperhomocysteinemia.Full blood count and coagulation profile
A complete blood count checks for anemia, platelet changes, and other blood abnormalities. Coagulation tests such as prothrombin time and activated partial thromboplastin time help assess clotting function. Abnormal results may show that homocysteine has already affected the blood and vessels and guide decisions about blood-thinning medicine.Liver and kidney function tests
Simple blood chemistry tests for liver enzymes and creatinine help judge organ function. Since CBS is mainly in the liver and homocysteine clearance involves the kidneys, these tests reveal whether organ disease is adding to the metabolic problem or affecting treatment choices.Enzyme activity assay in cultured cells or tissue
In specialized centers, CBS activity can be measured directly in liver tissue or cultured fibroblasts from a skin biopsy. These tests show how much working enzyme is present, help distinguish different forms of the disease, and confirm biochemical diagnosis when genetic results are unclear.
Electrodiagnostic tests
Electroencephalogram (EEG)
An EEG records tiny electrical signals from the brain using electrodes placed on the scalp. In people with seizures related to CBS deficiency, the EEG may show abnormal wave patterns. This helps confirm seizure type, guides anti-seizure drug choice, and monitors treatment response.Nerve conduction studies and electromyography (EMG)
Nerve conduction tests and EMG measure how well signals travel along nerves and muscles. While not required in every patient, these tests can be used when there is weakness, numbness, or suspected peripheral nerve involvement. They help rule out other neuromuscular diseases and document any nerve damage from vascular events.Evoked potential studies
Visual or somatosensory evoked potentials measure how fast signals move from the eyes or limbs to the brain. Delays in these tests can suggest subtle damage to visual pathways or brain regions from chronic high homocysteine or small strokes, even before changes are visible on ordinary imaging.
Imaging tests
Slit-lamp biomicroscopy and ophthalmic imaging
An eye specialist uses a slit-lamp microscope to closely inspect the cornea, lens, and front part of the eye. This detailed view shows the exact position of the lens and any zonular fiber damage. Detecting ectopia lentis in a young person with other suggestive signs strongly supports CBS deficiency.Skeletal X-rays and bone density scan
X-rays of the spine, chest, and long bones can show scoliosis, chest wall deformities, and bone thinning. A bone density scan (DEXA) measures how strong the bones are. These imaging tests confirm osteoporosis or deformities caused by long-term metabolic imbalance and are useful for monitoring response to treatment.Brain MRI and vascular imaging (CT or MR angiography)
Magnetic resonance imaging (MRI) of the brain can reveal old or recent strokes, white matter changes, or other damage from blood clots linked to high homocysteine. Vascular imaging of brain or body arteries and veins can show clots or narrowings. These tests are important in patients with headaches, seizures, or neurologic deficits to assess the full impact of CBS deficiency.
Non-pharmacological treatments (therapies and others)
These approaches work with medicines (they do not replace them). They are usually planned by a metabolic physician and dietitian.
Low-methionine, low-natural-protein diet
A carefully planned diet limits natural protein (meat, fish, eggs, dairy, many grains) to reduce intake of methionine, the amino acid that is converted to homocysteine.[1] The purpose is to lower homocysteine production and protect blood vessels, bones and eyes.[2] The main mechanism is simply less substrate entering the faulty CBS pathway, so less homocysteine accumulates.[3][1] [2] [3]
Methionine-free amino-acid formula
Many patients drink a special medical formula that contains all essential amino acids except methionine, plus extra vitamins and minerals.[1] Its purpose is to provide enough protein for growth without driving homocysteine levels higher.[2] Mechanistically, it replaces natural protein and supplies amino acids in a safe pattern that supports tissue repair while limiting toxic sulfur-amino-acid load.[3][1] [2] [3]
Extra dietary cysteine (under dietitian guidance)
Because CBS deficiency can reduce cystathionine-to-cysteine flow, some diets include extra cysteine or cystine as part of the medical formula.[1] The aim is to support glutathione production and antioxidant defenses, which depend on cysteine.[2] Mechanistically, cysteine bypasses the blocked CBS step and directly feeds into pathways that detoxify reactive oxygen species and maintain connective tissue.[3][1] [2] [3]
Strict hydration routines
Regular drinking plans (for example, small frequent fluids if allowed) help keep blood less viscous and may lower the chance of venous thrombosis.[1] The purpose is to reduce blood stasis and clot risk, especially during illness, heat, or after surgery.[2] Mechanistically, good hydration supports circulation, reduces hemoconcentration, and helps maintain kidney clearance of homocysteine and other solutes.[3][1] [2] [3]
Avoiding prolonged immobility
Patients are often advised to move frequently, especially on long trips or during hospital stays, to reduce clotting risk.[1] The purpose is to prevent pooling of blood in the legs and prevent deep-vein thrombosis.[2] Mechanistically, leg muscle contractions act as a “pump” that improves venous return, lowering venous pressure and preventing thrombus formation in a system already stressed by high homocysteine.[3][1] [2] [3]
Physiotherapy and posture training
Regular physiotherapy supports muscle strength, posture, joint alignment and balance, which can be affected by long limbs, scoliosis or osteoporosis.[1] The purpose is to reduce pain, prevent falls, and maintain daily independence.[2] Mechanistically, targeted exercises strengthen paraspinal and core muscles, improve bone loading patterns and may slow skeletal deformities that occur with weak connective tissue and fragile bones.[3][1] [2] [3]
Low-impact aerobic exercise
Activities such as walking, cycling or swimming (as approved by the doctor) can improve heart health, circulation and mood.[1] The purpose is to support cardiovascular fitness without excessive joint stress in osteoporotic bones.[2] Mechanistically, moderate aerobic activity improves endothelial function, enhances nitric oxide production and may counteract some vascular effects of high homocysteine, while also supporting weight control and insulin sensitivity.[3][1] [2] [3]
Occupational therapy and school support
Children with developmental or learning difficulties may benefit from occupational therapy, special education support and assistive technologies.[1] The purpose is to maximize independence in daily activities, school performance and social participation.[2] Mechanistically, structured cognitive and motor training helps the brain form new connections, compensates for deficits, and reduces the impact of attention, coordination or fine-motor problems linked with CBS deficiency.[3][1] [2] [3]
Vision correction and low-vision aids
Strong myopia, lens dislocation and retinal risks require regular eye care, high-quality glasses or contact lenses, and sometimes low-vision devices.[1] The purpose is to maintain safe vision for reading, mobility and daily tasks, while planning timely surgery if needed.[2] Mechanistically, optical aids refocus light on the retina despite lens displacement, while close monitoring allows early treatment of complications such as glaucoma or retinal detachment.[3][1] [2] [3]
Fall-prevention and bone-health strategies
Because of osteoporosis and long, thin bones, even minor falls can cause fractures.[1] The purpose of home safety checks, non-slip flooring, good lighting, and balance training is to reduce fracture risk.[2] Mechanistically, improving proprioception, muscle strength and environmental safety reduces trauma forces on fragile bone that has been weakened by abnormal collagen cross-linking related to hyperhomocysteinemia.[3]
[1] [2] [3]
Structured illness and surgery plans
During infections, fasting, operations or anesthesia, risk of clots can rise sharply.[1] Special peri-operative protocols plan IV fluids, early mobilization and sometimes temporary anticoagulation.[2] Mechanistically, careful anesthesia and post-operative care maintain cardiac output, avoid dehydration and minimize vascular injury, all of which help prevent thrombosis in a patient with high baseline homocysteine.[3]
[1] [2] [3]
Genetic counseling for families
Genetic counseling offers parents and adult patients clear explanations of inheritance, recurrence risk and reproductive options.[1] The purpose is to support informed decisions about carrier testing, prenatal diagnosis or pre-implantation genetic testing.[2] Mechanistically, identifying carriers and affected embryos does not change the gene itself, but can prevent new cases or ensure very early diagnosis, which greatly improves outcomes.[3]
[1] [2] [3]
(Items 13–20 could include school accommodations, psychological counseling, social-support groups, and careful avoidance of smoking and hormonal risk factors; for space, the key therapy ideas are summarized above.)
Drug treatments
Only a specialist can choose exact medicines and doses. Here is an overview of commonly used or clinically relevant drugs; most data come from rare-disease guidelines and regulatory labels.
Betaine anhydrous (Cystadane / generic betaine)
Class – methyl-group donor. Typical dosing – often ~6 g/day in 2 doses for older children and adults, or weight-based in younger patients, adjusted by homocysteine levels.[1] Purpose – to remethylate homocysteine back to methionine, lowering total homocysteine when CBS is deficient.[2] Mechanism – in the liver and kidney, betaine donates a methyl group via betaine-homocysteine methyltransferase, bypassing the blocked CBS pathway.[3] Side effects – fishy body odor, GI upset, rarely very high methionine if diet is too liberal.[4][1] [2] [3] [4]
Pyridoxine (vitamin B6)
Class – water-soluble vitamin, cofactor. Dosing – pharmacologic doses (for example 100–500 mg/day) are used in responsive patients and titrated by homocysteine response.[1] Purpose – to boost residual CBS enzyme activity in B6-responsive genotypes.[2] Mechanism – pyridoxal-5-phosphate is the active cofactor of CBS; giving high doses can stabilize some mutant enzymes and increase their catalytic activity.[3] Side effects – high chronic doses can cause sensory neuropathy; monitoring is needed.[4][1] [2] [3] [4]
Folic acid (vitamin B9)
Class – vitamin, cofactor in 1-carbon metabolism. Dosing – often 0.4–5 mg/day depending on age and pregnancy status.[1] Purpose – to support the remethylation pathway that converts homocysteine back to methionine via methionine synthase.[2] Mechanism – folate carries methyl groups as 5-methyltetrahydrofolate, which donates them to homocysteine in a vitamin B12-dependent reaction, lowering homocysteine.[3] Side effects – usually well tolerated; very high doses may mask B12 deficiency.[4][1] [2] [3] [4]
Cyanocobalamin or hydroxocobalamin (vitamin B12)
Class – vitamin, cofactor. Dosing – oral or intramuscular dosing schedules vary (for example monthly injections) based on B12 status.[1] Purpose – to correct B12 deficiency and support remethylation of homocysteine to methionine.[2] Mechanism – B12 is the cofactor for methionine synthase; adequate B12 allows folate-dependent remethylation to function efficiently.[3] Side effects – rare; occasional injection-site reactions or acne-like rash have been reported.[4][1] [2] [3] [4]
Riboflavin (vitamin B2)
Class – vitamin; cofactor for MTHFR and other enzymes. Dosing – low-to-moderate oral doses (for example 5–25 mg/day) are sometimes used.[1] Purpose – in some patients with combined hyperhomocysteinemia, riboflavin may support MTHFR activity and lower homocysteine, although evidence in pure CBS deficiency is limited.[2] Mechanism – FAD-dependent enzymes in folate metabolism rely on riboflavin; improving their activity may improve methyl-group cycling.[3] Side effects – harmless yellow urine, generally safe.[4][1] [2] [3] [4]
Low-dose aspirin (acetylsalicylic acid)
Class – antiplatelet agent. Dosing – low daily doses (for example 75–100 mg in adults) may be considered for high-risk vascular patients, as decided by specialists.[1] Purpose – to reduce platelet aggregation and lower risk of arterial thrombosis such as stroke or myocardial infarction.[2] Mechanism – irreversible COX-1 inhibition in platelets decreases thromboxane A2, reducing platelet clumping on damaged endothelium already stressed by high homocysteine.[3] Side effects – GI irritation, bleeding risk, rare allergy or asthma worsening.[4][1] [2] [3] [4]
Warfarin or other vitamin-K antagonists
Class – oral anticoagulants. Dosing – individualized based on INR monitoring.[1] Purpose – treatment and secondary prevention of venous thromboembolism in patients who already had clots.[2] Mechanism – inhibition of vitamin-K–dependent clotting factors reduces coagulation activity, countering the strong pro-thrombotic effect of high homocysteine.[3] Side effects – bleeding, drug–food interactions, need for frequent blood tests.[4][1] [2] [3] [4]
Low-molecular-weight heparin (e.g., enoxaparin)
Class – injectable anticoagulant. Dosing – weight-based, often used short-term around surgery, pregnancy or acute clots.[1] Purpose – bridge therapy or peri-operative thrombosis prevention in high-risk CBS-deficient patients.[2] Mechanism – accelerates antithrombin’s inhibition of factor Xa, rapidly reducing clot formation in venous circulation.[3] Side effects – bleeding, bruising, rare heparin-induced thrombocytopenia.[4][1] [2] [3] [4]
Bisphosphonates (e.g., alendronate) for osteoporosis
Class – anti-resorptive bone drugs. Dosing – standard osteoporosis regimens (for example weekly oral dosing) under specialist care.[1] Purpose – to strengthen bone and reduce fracture risk in severe osteoporosis caused by long-term metabolic disturbance.[2] Mechanism – bisphosphonates bind to bone mineral and are taken up by osteoclasts, inhibiting bone resorption and improving bone density.[3] Side effects – esophageal irritation, musculoskeletal pain, rare osteonecrosis of the jaw.[4][1] [2] [3] [4]
Vitamin D (cholecalciferol) and calcium (if needed)
Class – vitamin and mineral supplements. Dosing – individualized to reach normal vitamin D levels and safe calcium intake.[1] Purpose – to support bone mineralization and work together with diet and bisphosphonates to prevent fractures.[2] Mechanism – vitamin D improves intestinal calcium absorption and bone remodeling; adequate calcium provides building blocks for bone.[3] Side effects – excessive dosing can cause hypercalcemia, kidney stones and GI upset.[4]
[1] [2] [3] [4]
(Other drugs sometimes used include additional B-complex vitamins, pain control, anti-spasmodics, and drugs for specific complications. The core disease-directed agents remain betaine plus B6/B9/B12 and, when needed, anticoagulants.)
Dietary molecular supplements
Only a metabolic physician or dietitian should decide if any supplement is suitable.
Betaine powder as a medical food – Besides being a drug, betaine can be measured and mixed into liquids as a molecular supplement to drive homocysteine remethylation and lower plasma levels.[1] [2]
L-cysteine or cystine (in formula) – Supplying cysteine in the amino-acid mixture supports glutathione synthesis and collagen cross-linking, helping antioxidant defenses and connective tissue.[3] [4]
Methyl-folate (5-MTHF) – An activated folate form that directly donates methyl groups in remethylation pathways, bypassing some folate-processing steps and supporting homocysteine recycling.[5]
Methylcobalamin – An active B12 form used by methionine synthase; in some settings it may be preferred over cyanocobalamin to support one-carbon metabolism more directly.[5]
Riboflavin-rich B-complex – Combined B-vitamin formulas (B2, B6, B12, folate) may help when multiple cofactor deficiencies contribute to hyperhomocysteinemia.[3]
Omega-3 fatty acids (EPA/DHA) – These fats may modestly improve endothelial function and triglycerides and support heart health in people at high vascular risk, though they do not directly fix CBS deficiency.[6]
Antioxidant vitamins C and E (low-moderate dose) – May help neutralize oxidative stress related to high homocysteine, but evidence is limited and excessive doses are not recommended.[6]
Vitamin K2 (if not on warfarin) – In some osteoporosis protocols, K2 is explored for bone health, but it must be avoided with vitamin-K–antagonist anticoagulants.[7]
Probiotic blends – Experimental data suggest the gut microbiome can influence homocysteine and methyl-group metabolism, but evidence in CBS deficiency is still emerging.[8]
Specialized metabolic medical foods – Commercially prepared low-protein foods and methionine-free formulas contain carefully balanced amino-acid, vitamin and mineral profiles tailored for homocystinuria.[2]
[1] [2] [3] [4] [5] [6] [7] [8]
Regenerative, stem-cell and immunity-support approaches
Right now, there are no approved stem-cell or regenerative “drugs” specifically for CBS deficiency. Research is ongoing, and any such treatment would only be available in controlled clinical trials.[1][2] Instead, doctors focus on supporting the body’s own repair systems with good nutrition, bone-health therapies, and strong homocysteine control. Some future or experimental ideas include gene therapy to correct the CBS gene, liver-directed gene transfer, or combining metabolic control with bone-directed drugs, but these are not routine clinical options today.[3][4]
[1] [2] [3] [4]
Surgeries and procedures
Lens extraction and intra-ocular lens (IOL) implantation
When lens dislocation severely blurs vision, causes glaucoma, or threatens the retina, eye surgeons may remove the subluxated lens and implant an artificial lens.[1] The purpose is to restore clearer vision and prevent complications like glaucoma or retinal detachment.[2] Mechanistically, removing the unstable lens relieves traction on zonules and stabilizes the optical system, though careful peri-operative thrombosis prevention is needed.[3][1] [2] [3]
Orthopedic surgery for spine and chest deformities
Severe scoliosis, kyphosis or chest wall deformities may need corrective surgery, especially if they affect lung or heart function or cause major pain.[1] The purpose is to improve posture, breathing capacity and quality of life.[2] Mechanistically, instrumentation, fusion or osteotomy procedures realign the spine or chest wall, but require intensive thrombosis-prevention and bone-health management in CBS deficiency.[3][1] [2] [3]
Fracture fixation and orthopedic reconstruction
Osteoporotic fractures (hip, vertebra, long bones) may be treated with internal fixation, joint replacement, or vertebral procedures.[1] The purpose is to stabilize bone, relieve pain and restore mobility.[2] Mechanistically, surgical hardware redistributes mechanical loads across weak bone, but surgeons must plan carefully due to fragile skeleton and clotting risk.[3][1] [2] [3]
Vascular interventions for acute thrombosis
In severe clots, doctors may perform catheter-directed thrombolysis, thrombectomy, or place vena-cava filters.[1] The purpose is to restore blood flow, prevent pulmonary embolism and save organs or limbs.[2] Mechanistically, these procedures physically remove or dissolve the clot, buying time while long-term homocysteine-lowering and anticoagulation are optimized.[3][1] [2] [3]
Liver transplantation (very rare and extreme)
Because CBS is highly expressed in the liver, a transplanted liver with a normal CBS gene can theoretically normalize enzyme function and homocysteine metabolism.[1] This is reserved for exceptional cases where standard treatments fail or other liver disease is present.[2] Mechanistically, the new liver provides functional CBS, but transplantation carries major surgical risk and lifelong immunosuppression, so it is not standard first-line therapy.[3][1] [2] [3]
Prevention strategies
Newborn screening where available – detects elevated methionine or homocysteine so treatment can start before damage occurs.[1]
Carrier testing in high-risk families – identifies at-risk couples and siblings, guiding reproductive plans and early testing.[2]
Prenatal or pre-implantation genetic diagnosis – can prevent birth of another affected child or allow immediate post-birth treatment.[2]
Early, strict metabolic treatment in all diagnosed children – keeps homocysteine as low as possible to prevent eye, bone and vascular damage.[3]
Regular follow-up at a metabolic center – ensures doses, diet and lab targets remain correct as the child grows.[3]
Avoidance of smoking, high-dose estrogen contraceptives and other clot-risk factors – reduces additional vascular risk in adolescence and adulthood.[4]
Peri-operative thrombosis protocols – hydration, early mobilization and anticoagulation around surgeries or childbirth lower acute risk.[5]
Monitoring bone density – early detection of osteoporosis allows preventive therapy before fractures occur.[6]
Vision checks from childhood – ophthalmologic monitoring catches lens problems before permanent vision loss.[1]
Education of families and teachers – recognizing warning signs of stroke, DVT, sudden visual change or chest pain allows urgent care and better outcomes.[7]
[1] [2] [3] [4] [5] [6] [7]
When to see doctors
People with known or suspected deficiency of serine sulfhydrase should see a doctor or emergency service immediately if they notice sudden weakness on one side, difficulty speaking, sharp chest pain, severe shortness of breath, swollen painful leg, or sudden loss or blur of vision – these may be signs of stroke, pulmonary embolism, DVT or retinal problems.[1] Routine care should include frequent visits to a metabolic clinic, eye doctor, bone specialist and primary doctor for growth checks, homocysteine and methionine blood tests, eye exams and bone-density scans.[2] Any planned surgery, pregnancy, or long trip should be discussed ahead of time with the metabolic team so thrombosis-prevention steps can be organized.[3]
[1] [2] [3]
Diet: what to eat and what to avoid
Diet must be personalized by a metabolic dietitian; the list below is only a general idea.
What to eat (under specialist plan)
Prescribed methionine-free amino-acid formula – always the core of protein intake in many patients.
Fruits – many fruits are naturally low in protein and can often be eaten more freely while still following overall calorie limits.
Most vegetables – many vegetables give vitamins, fiber and minerals with modest protein content (except some higher-protein legumes).
Low-protein special breads, pastas and baking mixes – medical low-protein products allow variety without big methionine loads.[1]
Healthy oils (olive, canola, etc.) – provide energy without protein, supporting growth and weight maintenance.[2]
What to avoid or strictly limit (per dietitian)
Meat, poultry, fish – very high in methionine and need strong restriction in classical homocystinuria.[1]
Eggs and cheese – concentrated protein sources that quickly exceed daily methionine allowance.
Regular cow’s milk and high-protein dairy – usually replaced by special low-protein or measured alternatives.
Large servings of regular bread, pasta and cereals – contain notable protein and must be counted carefully within daily limits.
High-protein “health” products (protein bars, shakes, bodybuilding supplements) – often unsafe for patients using a methionine-restricted plan.
[1] [2]
Frequently asked questions (FAQs)
Is deficiency of serine sulfhydrase the same as classical homocystinuria?
Yes. “Serine sulfhydrase” is another name for the CBS enzyme, so its deficiency is the classic CBS-deficiency form of homocystinuria.[1]Can this disease be cured?
There is no simple cure yet, but many people live well with lifelong diet plus vitamins and betaine, and sometimes anticoagulants, keeping homocysteine near-normal and reducing complications.[2]Why is homocysteine so dangerous?
High homocysteine damages the inner lining of blood vessels, increases oxidative stress and disturbs clotting, making arteries and veins much more likely to form clots.[3]What is B6-responsive vs B6-non-responsive disease?
In some gene variants, high-dose vitamin B6 makes CBS work better, dramatically lowering homocysteine (B6-responsive).[4] In others, enzyme activity barely improves, so diet plus betaine are essential (B6-non-responsive).[4]Why do many patients need betaine as well as diet and vitamins?
Even with strong diet control, homocysteine may stay high. Betaine provides an extra pathway that remethylates homocysteine, often bringing levels closer to target.[5]Does every patient need anticoagulation like warfarin?
No. Long-term anticoagulation is usually reserved for patients who already had major clots or have very high risk; others may only need careful metabolic control and short-term anticoagulation during surgery or pregnancy.[6]Will children with homocystinuria grow normally?
With early diagnosis, good metabolic control and adequate calories and safe protein, many children can have near-normal growth and development, though some may still have learning or skeletal issues.[2]Why are eye problems so common?
Homocysteine weakens the connective tissue fibers that hold the lens and support the eye, leading to lens dislocation, myopia and higher risk of retinal problems.[7]Is pregnancy possible for women with CBS deficiency?
Yes, but pregnancy is considered high risk; it requires tight metabolic control, folate and B12 optimization, and careful thrombosis-prevention plans coordinated by obstetric and metabolic specialists.[8]Can normal school and sports be possible?
Many children attend regular school with some supports. Non-contact, low-impact sports are often possible, but activities with high fracture or head-injury risk may be limited by the medical team.[2]How often are blood tests needed?
Early in treatment, blood tests for homocysteine, methionine and nutritional status may be done frequently (for example every 1–3 months), then less often once levels are stable; schedules are highly individual.[3]What happens if treatment is stopped?
Homocysteine typically rises again, increasing the risk of eye damage, bone fragility and dangerous clots, so treatment is generally lifelong.[2]Are there new treatments being researched?
Researchers are exploring improved betaine formulations, better dietary tools, and experimental gene-based or liver-targeted therapies, but so far, standard care remains diet plus vitamins and betaine.[9]Is this the same as folate or B12 deficiency homocystinuria?
No. Several different defects can cause high homocysteine; CBS deficiency is one. Other forms involve remethylation defects or vitamin deficiencies and are treated somewhat differently, though all aim to lower homocysteine.[3]Who should coordinate care?
Ideally, a metabolic geneticist and specialized dietitian coordinate care, with close support from ophthalmology, orthopedics, hematology and primary care. This team approach gives the best chance to prevent complications and maintain quality of life.[1][2]
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: January 27, 2025.
